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Stroke is the second most common cause of both death and disability-adjusted life-years worldwide, but its molecular mechanisms remain poorly understood, which makes developing new treatments challenging. Linking the study’s results with extensive biological databases provides new clues on stroke mechanisms and illustrates the potential of genetics to identify drug targets for stroke therapy.

Stroke can originate from alterations in various parts of the vasculature including large arteries, small arteries, the heart, and the venous system and the researchers found genetic risk factors implicated in each of these mechanisms. They showed that some genetic risk factors contribute to specific mechanisms and others to stroke susceptibility at large. They also found shared genetic influences between stroke caused by vessel occlusion which is the most common cause of stroke, and stroke caused by rupture of a blood vessel, the most catastrophic cause of stroke, often thought to have opposite mechanisms.

The study was based on DNA samples of 520,000 European, North- and South American, Asian, African, and Australian participants of whom 67,000 had a stroke. These were derived from 29 large studies. From the millions of genetic variants analysed, 32 independent genomic regions were shown to be associated with stroke of which two thirds are novel.

When the researchers looked closely at the genomic areas pinpointed in the study, they noticed that several of them overlap with genomic areas known to be implicated in related vascular conditions such as atrial fibrillation, coronary artery disease, venous thrombosis, or vascular risk factors, especially elevated blood pressure, and less so hyperlipidemia.

By adding data on gene expression, protein expression, and other characteristics in multiple cell types and tissues compiled by their co-investigators the researchers obtained first insights into the specific genes, molecular pathways, and cell and tissue types through which the new genetic risk factors cause stroke.

The researchers found that the genes they identified are enriched in drug targets for antithrombotic therapy, used to re-open occluded blood vessels in patients with acute stroke or to prevent vascular events including stroke. Jemma Hopewell, Associate Professor of Genetic Epidemiology and Clinical Trials, co-author and Chair of the METASTROKE collaboration, which contributed to the new study said ‘These findings illustrate the potential of genetics for drug discovery.’

The study was conducted by members of MEGASTROKE, a large international collaboration of research groups that are part of the International Stroke Genetics Consortium.